Introduction

Acetylcholinesterase (AChE) is a cholinergic enzyme primarily found at postsynaptic neuromuscular junctions, especially in muscles and nerves. It immediately breaks down or hydrolyzes acetylcholine (ACh), a naturally occurring neurotransmitter, into acetic acid and choline.[1] The primary role of AChE is to terminate neuronal transmission and signaling between synapses to prevent ACh dispersal and activation of nearby receptors. Organophosphates inhibit AChE. They are an important component of pesticides and nerve agents.

Issues of Concern

Organophosphates are acetylcholinesterase inhibitors with the potential for exposure and toxicity related to their use as pesticides. Due to widespread use, organophosphates are one of the most common causes of poisoning in the world from agricultural, accidental, or suicidal exposure.[2] Exposure to organophosphates may cause symptoms such as confusion, headache, and impaired memory and may have neurotoxic effects from repeated exposure. Irreversible acetylcholinesterase inhibitors used as insecticides or nerve agents in warfare pose significant toxicity. These agents induce a cholinergic crisis which includes any combination of the following:

• Muscarinic effects, such as miosis, increased secretions (salivation, lacrimation), diarrhea, urination
• Nicotinic effects, such as muscle fasciculations and neuromuscular blockade
• Central effects: bradycardia

Organophosphate poisoning is treatable with atropine, an antimuscarinic that reduces the effects of ACh surplus.[2] Atropine should be given initially at 2 to 5mg IV for adults and 0.05 mg/kg IV for children. Doubling the dose every 3 to 5 minutes until symptoms begin to cease is also appropriate if no relief is noted after the first dose.[3]

Alzheimer dementia (AD) is a prevalent disease that affects memory and cognition. The pathophysiology of cognitive impairment associated with AD has been attributed to a loss of cholinergic neurons.[4] Histologically, B-amyloid plaques and neurofibrillary tangles interrupt synaptic signaling, leading to neuronal cell death.[5] Since the 1990s, AChE inhibitors have shown some benefit for Alzheimer disease.[6] Inhibition of AChE results in a decreased breakdown and subsequent accumulation of acetylcholine. This excess acetylcholine leads to increased stimulation of muscarinic and nicotinic receptors, which provides some therapeutic relief for the memory deficits in AD.[4] AChE inhibitors have various levels of penetrance through the blood-brain barrier (BBB). Donepezil, rivastigmine, and tacrine are commonly used drugs for Alzheimer disease with good blood-brain barrier penetration. This activity is in contrast to the carbamate AChE inhibitors, neostigmine or pyridostigmine, which are charged quaternary structures at physiologic pH that prevent the crossing of the blood-brain barrier.[7] While the benefits of acetylcholine modulation therapy are promising, further studies are necessary due to the potential for accumulation of AChE, which may potentially interact with B-amyloid plaques and cause more neurotoxicity than B-amyloid alone.[4][8]

Cellular Level

As an enzyme, acetylcholinesterase exists as a monomer that often polymerizes into a dimer with a disulfide bond. Along with Van der Waals forces, two dimers may be linked to become tetramers. The tetramers assemble and bind themselves to what is described as “tails” made up of three strands. Chemically and immunologically, these tails structurally resemble collagen and may be broken down by collagenases. With an additional disulfide bond, the dimers of the tetramer link to each tail. A study by Brimijoin et al. describes the six combinations of AChE: three forms of the globular structure (monomers, dimers, tetramers) and three forms of tetramers (tailed, double, triple).[9] Globular AChE is labeled with a “G,” and tailed AChE is labeled with an “A.” Different forms have numerical subscripts associated with each letter to denote the number of their catalytic subunits. For example, a globular monomer is “G1,” and a globular tetramer is “G4”; meanwhile, a triple tetramer with a tail is “A12.”[9]

Development

Although the primary function of AChE is to terminate neural transmission, investigators have found that AChE also plays a role in neural development. Embryologically, AChE is intricately involved in the development of the nervous system and is expressed by developing neurons and during periods of axonal growth (a time in which enzymatic activity does not seem to be most important). In the peripheral nervous system of chicks, transient AChE activity was found to be locally present in the dorsal root ganglions. These findings suggest that during fetal development, AChE contributes to morphogenesis in addition to its main enzymatic function.[10]

Organ Systems Involved

Acetylcholinesterase is known to be distributed in nervous tissue such as the brainstem, cerebellum, and peripheral and autonomic nervous systems. Skeletal muscle also contains AChE with distribution patterns seemingly related to the type of muscle (fast versus slow twitch) and their specific function.[9]

The presence and function of AChE on red blood cells are less commonly known. Blood group antigens reside on the outer lipid bilayer of red blood cells for convenient antibody recognition. In the same regard, AChE is also present on red blood cell membranes.[11]

Function

The neurotransmitter acetylcholine is released when a neural signal propagates and excites or activates a cellular membrane. Consequently, the ACh receptor undergoes a conformational change, and the membrane releases calcium ions. These calcium ions play a role in exciting the fibers of nerves and muscles by triggering an additional change in phospholipids. Essentially, the downstream effect of a signal initiated with ACh results in the amplification and propagation of cellular signaling.[12]

Mechanism

The interaction of acetylcholinesterase with the substrate acetylcholine results in the breakdown, hydrolysis, and inactivation of acetylcholine and subsequent control of the amount of ACh at the synapse. AChE is a serine hydrolase that creates a tetrahedral intermediate through acid-base reactions with a catalytic triad (serine, histidine, acid residue).[8] Histidine allows for the transference of a proton between the oxygen molecules in serine and ACh, thereby removing choline to form a new acylated serine. When the acylated serine is deacylated, the regeneration of free AChE begins. In this reaction, aspartate stabilizes the protonated histidine, which releases acetic acid and a new, free enzyme. The interaction between amino acid residues (tyrosine, phenylalanine, tryptophan) that make up a peripheral anionic site influences the conformational binding of ACh to that site.[1]

Related Testing

Positron emission tomography (PET) imaging of cortical AChE activity in vivo has been used to measure the efficacy of dementia therapy. There are reports of decreased activity of acetylcholinesterase in patients with Alzheimer disease. By measuring AChE activity and using it to gauge cholinergic innervation expressed by axons and nerves, investigators may configure and assess the efficacy of cholinesterase inhibitors as it contributes to the management of Alzheimer disease.[13]

Pathophysiology

The human brain has a confluence of cholinergic neurons that project to various cortical areas. These neurons control attention, thinking, and processing of stimuli. Not only do cholinergic neurons span the forebrain, but they also encompass the brainstem and thalamus (such as the reticular nucleus), which are responsible for consciousness and attention. In the context of Alzheimer dementia as a neurodegenerative disease, these cholinergic neurons have defective projections that correlate with the classic symptoms of cognitive slowing and decline.[13] The disease is well known for declining short-term memory, atrophy of the cerebrum, B-amyloid plaques, tangles, and tau protein deposits.[1]

Clinical Significance

Patients with Alzheimer disease often receive treatment with acetylcholinesterase inhibitors that mitigate symptoms by hindering ACh turnover. In effect, lingering levels of ACh help recalibrate the neurotransmitter to appropriate and adequate levels.[5] Inhibition of AChE raises the concentration of ACh at the synaptic junction and allows for the potentiation of the signal. This action ultimately reduces the amount of choline uptake and increases the number of muscarinic M2 receptors. In those treated with AChE inhibitors, a deceleration of the progression of the disease, as well as an increased attention span, has been reported. However, no significant signs of increased short-term memory have been noted in the current literature.[1]

Despite the apparent benefit of AChE inhibitors for the management of Alzheimer disease, recent studies have stated that the application of such inhibitors fails to address the pathology in its entirety. Nordberg et al. have found that some AChE inhibitors, such as donepezil or galantamine, show increased levels of AChE in CSF.[14] An imbalance of AChE can worsen Alzheimer dementia, as complexes of AChE-amyloid-B show higher levels of toxicity than amyloid-B plaques alone.[4] Such findings warrant a reassessment of current treatment options for the disease, as these drugs may have an underlying potential to worsen the pathologic state in Alzheimer disease.[8]